proton pump inhibitors

ASEMINARGASTRIC PROTON PUMP INHIBITORS : 

ASEMINARGASTRIC PROTON PUMP INHIBITORS PRESENTED BY ABDUL RAZZAQ M-PHARMACY LUQMAN COLLEGE OF PHARMACY, GULBARGA SUBMITED TO Mr. GUBBI SUDHEENDARA PROFESSOR DEPARTMENT OF PHARMACHEMISTRY. LUQMAN COLLEGE OF PHARMACY, GULBARGA 2009-2010

CONTENTS : 

CONTENTS INTRODUCTION GASTRIC ACID SECRETION AND REGULATION IRREVERSIBLE GASTRIC PROTON PUMP INHIBITORS.

INTRODUCTION : 

INTRODUCTION Numerous compounds are available to treat the gastric ulcer. Healing of ulcer may be achieved by at least 3 different modes. Stimulation of regeneration of cell surrounding the ulcer base. E.g. - licorice extract 2) By using coating agents Eg-sucralfate or bismuth 3) By inhibiting gastric acid secretion or by antacid. Clinical trials & clinical experiences have demonstrated that inhibition of gastric acid secretion is superior in promoting ulcer healing & reliving ulcer symptoms to all the other possible methods mentioned above. HISTORY H2 antagonist & ppi has different mechanism of action. In 1974 timoprazole was invented then picoprazole & omeprazole invented in 1976.

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TIMOPRAZOLE PICOPRAZOLE

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After different kind of substitution leads to new drug PENTOPRAZOLE RABIPRAZOLE

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DISUPRAZOLE

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REGULATION OF GASTRIC ACID SECRETION Terminal enzyme H+K+ATPase (proton pump) secretes H+ ions in apical canaliculi of parietal cell. These parietal cell activated by histamine, Ach, gastrin via receptor on basolatoral membrane H2 receptors activate H+ K+ATPase by generating cAMP, muscarinic & also via the phospolipasase C-IP3-DAG pathway that mobilizes Ca2+ which activates the proton pump. & gastrin cholecystokinins receptors

Phases of secretion : 

Phases of secretion Cephalic phase The sight, smell, taste & swallowing of food causes central stimulation of vogues nerve leading to Ach releases from synapses within the fluidic & antral regions. Gastric phase Gastric is main mediator of acid secretion acid secretion occurs in response to both the presence of nutrients physical destintions produced by food entering in stomach. Chemical constituents of meal are strongest stimulant of gastrin release and acid out put during gastric phase with peptides and amino acids being greater stimulants of gastrin than proteins, carbohydrates and fats. Intestinal phase A small amount of acid is secreted because of numerous inhibitory mechanism stimulated by the presence of Nutrients with in the intestinal lumen Stimulation of stomatostatin releases from D cell in antrum of stomach inhibits the release of gastrin from G cell and thus reduces gastric acid secretion

Disorders : 

Disorders Disorders associated with elevated acid secretion Zollinger Ellison Syndrome In this disease a non beta cell tumour of the pancreatic islets may produce gastrin in quantity sufficient to stimulate secretion of gastric acid to life threatening level. Gastro esophageal reflux disorder It is disorder of defense mechanism at the esophageal junction which is caused by regurgitation of gastric content especially at gastric acid. 3. Helicobacter pylori (H Pylori) 40% peoples over 40 yrs age and peptic ulcer disease patient infected by H pylori. In duodenal ulcer patient H pylori infection causes the inflammation of antral gastric mucosa in gastric acid secretion.

CLASSIFICATION : 

CLASSIFICATION Gastric acid inhibitors H2 antagonist (antihistaminic) E.g.-cimitidine, ranitidine famotidine roxatidine loxatidine. Proton pump inhibitors Eg-omeprazole, lansoprazole, pantoprazole, rabeprazole, esmoprazole. Anticholinergics E.g.-pirenzepines, propanthelines, oxyphenonium. Prostaglandin analogues Eg-misoprostol, enrpostil, rioprostil.

IDEAL PROPERTIES OF DRUG USED IN PEPTIC ULCER : 

IDEAL PROPERTIES OF DRUG USED IN PEPTIC ULCER Drug should be chemically stable so that it should be stable in acidic condition. Drug should be bioavailable so that optimum concentration can be achieved. Bioavailability within sufficient time should be there to give Better results Drug should show desirable action without side effect or Minimum side effects.

H2 ANTAGONIST : 

H2 ANTAGONIST STRUCTURAL ACTIVITY RELATIONSHIP Imidazole ring 1) Methylation at 5 position leads to arterial histamine selective agonistic action R=CH3. 2)N-Guanylhistamin weak antagonist.

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3) Increasing l of side length of side chain from 2 to 4 carbon couple with replacement of guanidine group by the neutral methyl thiourea function Burimamide. 4) N Imidazo tautomer has prominent activity. 5) Thiourea structural feature is eliminated by replacing the thiourea sulphur with cyano-imino function to produce cimetidine which is effective gastric antisecretory agent that promotes the healing of duodenal ulcer.

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Cimitidine Thiazole ring Famotidine Famotidine is competitive inhibitor of histamine H2 receptors & inhibits basal & nocturnal gastric secretion.

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C) Furan ring It is an amino alkyl furan derivative Ranitidine

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PROTONPUMP INHIBITORS (PPIS) OMEPRAZOLE

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PRODRUG ACTIVATION

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Omeprazole is a prodrug which undergoes chemical activation in acidic environment. ATPase-SH group (sulfydryl group) on proton pump prevents further release of H+

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SAR 1) Substituted pyridine ring, The substituted benzimidazole moiety & methyl sulfinyl chain connecting these two is essential for the biological effect. 2) Biological activity & chemical stability largely depends on their substitution pattern.

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3) Pyridine substitution TIMOPRAZOLE PICOPRAZOLE Pyridine substitution compared to timoprazole 4-methoxy group in the pyridine ring increases the biological activity by enhancing nucleophilicity of pyridine nitrogen atom. A 4-fluro alkoxy substitution combining lipophilicity & electron demanding properties results strong inhibitory activity.

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Pyridine substitution compared to timoprazole 4-methoxy group in the pyridine ring increases the biological activity by enhancing nucleophilicity of pyridine nitrogen atom. A 4-fluro alkoxy substitution combining lipophilicity & electron demanding properties results strong inhibitory activity. E.g.-LANSOPRAZOLE SAVIPRAZOLE

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3) Benzimidazole substitution Unsaturated benzimidazole moiety shows irreversible gastric proton pump inhibition. Benzimidazole substitution by electron demanding group leads to strong activity. Benzimidazole substitution by electron accepting group leads to less activity.

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C) ANTICHOLINERGICS Pirenzepine It inhibits gastric secretion without side effects (atropine side effects due to M2 M3 receptor blockage ) it is nearly equally effective as cimitidine in reliving peptic ulcer pain & promoting ulcer healing . The exact location of M1 receptor through which pirenzepines exerts its antisecretory action is not definite.

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2) Propantheline bromide 3) Oxyphencyclamine

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4) Oxyphenonium

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D) PROSTAGLANDINE ANALOGUES Role of prostaglandin 1) Inhibits the acid secretion by opposing the cAMP generation & gastrin release. 2) Prostaglandin markedly reduces acid secretion in stomach. Volume of juice & pepsins content are also decreses. 3) It inhibit fasting as well as stimulated secretion (by feeding, histamine gastrine). 4) As antisecretory agent PGE2 more potent than PGI2. 5) PGI2 regulates the gastric mucosal blood flow.

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Test assay for studying gastric acid inhibition The biochemical characterization of a compound for its inhibitory effectiveness on gastric acid secretion requires in vivo studies in laboratory animals as well as in vitro studies in isolated stomach, fundic mucosa, gastric glands, cells, & sub cellular functions (enzymes, receptors). In vitro studies are performed to elucidate the mechanism of action of any Compound of interest, whereas animal studies are used to proof a compounds practical usefulness. Normally in vitro studies are used to elucidate the M.O.A of compound active in vivo or to screen for a defined target. In the latter case, A compound active in vitro with a defined mechanism of action.

IN VIVO : 

IN VIVO Gastric acid secretion can be studied in vivo in rats & dogs. Conscious rat models are rats which have a chronic gastric fistula are pylorus ligated or involve anesthetized rats with stomach lumen perfusion. Gastric acid secretion can be studied under basal conditions as well as during stimulation Of gastric acid secretion following an intravenous infusion or sub cutanious Injection of a secretagogue i.e. carbochol, or histamine from the biomedical Experience with different kinds of gastric acid inhibitors, the conscious dog

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Seems to be the most relevant animal species for the production of antisecretory potential of a test compound in humans Gastric acid secretion can be studies in a dog that has been surgical prepared with A chronic gastric fistula or with heidenhain pouch. This is mostly done during stimulatory condition, e.g. a continuous intravenous infusion with lust amine as the heidenhain pouch is vagally denervated, and stimulation of gastric acid secretion with gastrin needs a small amount of carbachol. Originally cytoprotection was defined as potential of test compound to protect the gastric mucosa of rat against necrotizing agents, such as, absolute ethanol 0.6 N Hcl 0.2 NaOH, 25% sodium chloride or boiling water in nonantisecretory doses several prostaglandins caused cytoprotection particularly in rats over a dose range which had no antisecrtory activity however, clinical experiences with prostaglandins has shown that ulcer healing is only achieved at antisecretory doses therefore it seems very likely that the cytoprotective property of a compound in rats has very limited

IN VITRO : 

IN VITRO The effect of gastric proton pump inhibitor on H+K+ATPase activity (ATP cleavage) can be studied in vitro with partially purified H+K+ATPase preparation. This assay has been used more effectively to study the mechanism of action of gastric proton pump inhibitors in detail than to study SAR. Omeprazole (PPI) need acid activation preincubation period at a pH no lower than about 6 hr was used to convert test compound to active principle Acid formation is on in vitro has been studied very intensively In isolated parietal cells from guinea pigs, dogs, rabbits as well as whole gastric glands from rabbits and humans. Measurement of acid formation was achieved indirectly by means of accumulation of weak base 14C-amino pyrine (pka 5.0) within secretary compartment of paritial cells. Due to its nature as a weak base 14C- amino pyrine accumulates in acidic compartments At pH 7.4 (test medium & cytosol of parietal cells ) it can pass freely through biological memb.in its unionized from but becomes trapped immediately within secretary cannaliculi because of ionization

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Furthermore O2 consumption correlates with acid formation &has been very useful to identify artifact’s of inhabitation of 14c-aminopyrine accumulation through neutralization of acidic compartment by basic nature of test compound during artifact condition 14C-aminopyrine accumulation is reduced by neutralization of acidic compartment by test compound even when proton pump is still active & O2 consumption is uninhibited.

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THANK YOU WISH YOU “HAPPY DIWALI”

REFERENCES : 

REFERENCES 1) Burger’s; medicinal chemistry &drug discovery, Volume-II, therapeutic agents, 5th edition, Edited by E.wolff, Awiley-interscience publication. Page no-120-134. 2) Textbook of drug design & discovery, 3rd edition, povl-krogsgaard Larsen, edited by Tommy lilgefors & Ulf Madsen Page no-329,452-454. 3) Smith & William’s, Introduction to the principles of drug design & action, 4th edition, Edited by John Smith Taylor & Francis. Page no-167-169,540-542. 4)Comprehensive Medicinal chemistry-II, Volume-VI, Elsevier 2006, Editors-in-chief; John B Taylor & David J Triggle. Pg.no-589-595,678.

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